Modulation of innate immune response to mRNA vaccination after SARS-CoV-2 infection or sequential vaccination in humans.

mRNA vaccines are likely to become widely used for the prevention of infectious diseases in the future. Nevertheless, a notable gap exists in mechanistic data, particularly concerning the potential effects of sequential mRNA immunization or preexisting immunity on the early innate immune response triggered by vaccination. In this study, healthy adults, with or without documented prior SARS-CoV-2 infection, were vaccinated with the BNT162b2/Comirnaty mRNA vaccine. Prior infection conferred significantly stronger induction of proinflammatory and type I IFN-related gene signatures, serum cytokines, and monocyte expansion after the prime vaccination. The response to the second vaccination further increased the magnitude of the early innate response in both study groups. The third vaccination did not further increase vaccine-induced inflammation. In vitro stimulation of PBMCs with TLR ligands showed no difference in cytokine responses between groups, or before or after prime vaccination, indicating absence of a trained immunity effect. We observed that levels of preexisting antigen-specific CD4 T cells, antibody, and memory B cells correlated with elements of the early innate response to the first vaccination. Our data thereby indicate that preexisting memory formed by infection may augment the innate immune activation induced by mRNA vaccines.

Profiling the dysregulated immune response in sepsis: overcoming challenges to achieve the goal of precision medicine.

Sepsis is characterised by a dysregulated host immune response to infection. Despite recognition of its significance, immune status monitoring is not implemented in clinical practice due in part to the current absence of direct therapeutic implications. Technological advances in immunological profiling could enhance our understanding of immune dysregulation and facilitate integration into clinical practice. In this Review, we provide an overview of the current state of immune profiling in sepsis, including its use, current challenges, and opportunities for progress. We highlight the important role of immunological biomarkers in facilitating predictive enrichment in current and future treatment scenarios. We propose that multiple immune and non-immune-related parameters, including clinical and microbiological data, be integrated into diagnostic and predictive combitypes, with the aid of machine learning and artificial intelligence techniques. These combitypes could form the basis of workable algorithms to guide clinical decisions that make precision medicine in sepsis a reality and improve patient outcomes.

Risk and outcomes of COVID-19 in patients with oxygen-dependent chronic respiratory failure- a national cohort study.

BACKGROUND: We aimed to evaluate cumulative occurrence and impact of COVID-19 in patients with chronic respiratory failure (CRF) treated with long-term oxygen therapy (LTOT). MATERIAL AND METHODS: Data were obtained from the SCIFI-PEARL study on the entire Swedish population and on patients with oxygen-dependent CRF and no COVID-19 diagnosis before start of LTOT. Analyses were performed for three time periods; pre-alpha (Jan-Dec 2020), alpha (Jan-Mar 2021) and delta/omicron (Apr 2021-May 2022). Cumulative incidence of laboratory-verified COVID-19 was compared between patients with CRF and the general population. Risk factors for severe (hospitalised) to critical (intensive care, or death ≤30 days after infection) COVID-19, and the impact of COVID-19 on one-year mortality, were analysed using multivariable Cox regression. RESULTS: Cumulative incidence of COVID-19 was higher in patients with CRF than in the general population during the pre-alpha period (6.4%/4.9%, p = 0.002), but less common during the alpha and delta/omicron periods (2.9%/3.8% and 7.8%/15.5%, p < 0.0001 for both). The risk of severe/critical COVID-19 was much higher in CRF patients during all periods (4.9%/0.5%, 3.8%/0.2% and 15.5%/0.5%, p < 0.0001 for all). Risk factors for COVID-19 infection in people with CRF were higher age, cardiovascular and renal disease, and COVID-19 was associated with increased one-year mortality following infection in the pre-alpha (HR 1.79; [95% CI] 1.27-2.53) and alpha periods (1.43; 1.03-1.99). CONCLUSION: Patients with CRF had higher risk of severe/critical COVID-19 than the general population. COVID-19 infection was associated with excess one-year mortality.

Design of a national patient-centred clinical pathway for sepsis in Sweden.

BACKGROUND: The World Health Organization has adopted a resolution on sepsis and urged member states to develop national processes to improve sepsis care. In Sweden, sepsis was selected as one of the ten first diagnoses to be addressed, when the Swedish government in 2019 allocated funds for patient-centred clinical pathways in healthcare. A national multidisciplinary working group, including a patient representative, was appointed to develop the patient-centred clinical pathway for sepsis. METHODS: The working group mapped challenges and needs surrounding sepsis care and included a survey sent to all emergency departments (ED) in Sweden, and then designed a patient-centred clinical pathway for sepsis. RESULTS: The working group decided to focus on the following four areas: (1) sepsis alert for early detection and management optimisation for the most severely ill sepsis patients in the ED; (2) accurate sepsis diagnosis coding; (3) structured information to patients at discharge after sepsis care and (4) structured telephone follow-up after sepsis care. A health-economic analysis indicated that the implementation of the clinical pathway for sepsis will most likely not drive costs. An important aspect of the clinical pathway is implementing continuous monitoring of performance and process indicators. A national working group is currently building up such a system for monitoring, focusing on extraction of this information from the electronic health records systems. CONCLUSION: A national patient-centred clinical pathway for sepsis has been developed and is currently being implemented in Swedish healthcare. We believe that the clinical pathway and the accompanying monitoring will provide a more efficient and equal sepsis care and improved possibilities to monitor and further develop sepsis care in Sweden.

High prevalence of persistent symptoms and reduced health-related quality of life 6 months after COVID-19.

Background: The long-term sequelae after COVID-19 constitute a challenge to public health and increased knowledge is needed. We investigated the prevalence of self-reported persistent symptoms and reduced health-related quality of life (HRQoL) in relation to functional exercise capacity, 6 months after infection, and explored risk factors for COVID-19 sequalae. Methods: This was a prospective, multicenter, cohort study including 434 patients. At 6 months, physical exercise capacity was assessed by a 1-minute sit-to-stand test (1MSTST) and persistent symptoms were reported and HRQoL was evaluated through the EuroQol 5-level 5-dimension (EQ-5D-5L) questionnaire. Patients with both persistent symptoms and reduced HRQoL were classified into a new definition of post-acute COVID syndrome, PACS+. Risk factors for developing persistent symptoms, reduced HRQoL and PACS+ were identified by multivariable Poisson regression. Results: Persistent symptoms were experienced by 79% of hospitalized, and 59% of non-hospitalized patients at 6 months. Hospitalized patients had a higher prevalence of self-assessed reduced overall health (28 vs. 12%) and PACS+ (31 vs. 11%). PACS+ was associated with reduced exercise capacity but not with abnormal pulse/desaturation during 1MSTST. Hospitalization was the most important independent risk factor for developing persistent symptoms, reduced overall health and PACS+. Conclusion: Persistent symptoms and reduced HRQoL are common among COVID-19 survivors, but abnormal pulse and peripheral saturation during exercise could not distinguish patients with PACS+. Patients with severe infection requiring hospitalization were more likely to develop PACS+, hence these patients should be prioritized for clinical follow-up after COVID-19.

Risk factors for impaired respiratory function post COVID-19: A prospective cohort study of nonhospitalized and hospitalized patients.

BACKGROUND: Severe COVID-19 increases the risk for long-term respiratory impairment, but data after mild COVID-19 are scarce. Our aims were to determine risk factors for reduced respiratory function 3-6 months after COVID-19 infection and to investigate if reduced respiratory function would relate to impairment of exercise performance and breathlessness. METHODS: Patients with COVID-19 were enrolled at the University Hospitals of Umeå and Örebro, and Karlstad Central Hospital, Sweden. Disease severity was defined as mild (nonhospitalized), moderate (hospitalized with or without oxygen treatment), and severe (intensive care). Spirometry, including diffusion capacity (DLCO ), was performed 3-6 months after hospital discharge or study enrollment (for nonhospitalized patients). Breathlessness (defined as ≥1 according to the modified Medical Research Council scale) and functional exercise capacity (1-min sit-to-stand test; 1-MSTST) were assessed. RESULTS: Between April 2020 and May 2021, 337 patients were enrolled in the study. Forced vital capacity and DLCO were significantly lower in patients with severe COVID-19. Among hospitalized patients, 20% had reduced DLCO , versus 4% in nonhospitalized. Breathlessness was found in 40.6% of the participants and was associated with impaired DLCO . A pathological desaturation or heart rate response was observed in 17% of participants during the 1-MSTST. However, this response was not associated with reduced DLCO . CONCLUSION: Reduced DLCO was the major respiratory impairment 3-6 months following COVID-19, with hospitalization as the most important risk factor. The lack of association between impaired DLCO and pathological physiological responses to exertion suggests that these physiological responses are not primarily related to decreased lung function.

Serum concentration of extracellular cold-inducible RNA-binding protein is associated with respiratory failure in COVID-19.

Uncontrolled release of damage-associated molecular patterns (DAMPs) is suggested to be a major trigger for the dysregulated host immune response that leads to severe COVID-19. Cold-inducible RNA-binding protein (CIRP), is a newly identified DAMP that aggravates inflammation and tissue injury, and induces respiratory failure in sepsis. Whether CIRP contributes to the pathogenesis of respiratory failure in COVID-19 has not yet been explored. Aim: To investigate if the concentration of extracellular CIRP (eCIRP) in serum associates with respiratory failure and lung involvement by chest computed tomography (CT) in COVID-19. Methods: Herein we report a prospective observational study of patients with COVID-19 included at two University Hospitals in Sweden between April 2020 and May 2021. Serum from hospitalized patients in Örebro (N=97) were used to assess the association between eCIRP and the level of respiratory support and its correlation with pulmonary involvement on chest CT and inflammatory biomarkers. A cohort of hospitalized and non-hospitalized patients from Umeå (N=78) was used as an external validation cohort. The severity of disease was defined according to the highest degree of respiratory support; mild disease (no oxygen), non-severe hypoxemia (conventional oxygen or high-flow nasal oxygen, HFNO <50% FiO2), and severe hypoxemia (HFNO ≥50% FiO2, mechanical ventilation). Unadjusted and adjusted linear regression was used to evaluate peak eCIRP day 0-4 in respect to severity, age, sex, Charlson comorbidity score, symptom duration, and BMI. Results: Peak eCIRP concentrations were higher in patients with severe hypoxemia and were independently associated with the degree of respiratory support in both cohorts (Örebro; p=0.01, Umeå; p<0.01). The degree of pulmonary involvement measured by CT correlated with eCIRP, rs=0.30, p<0.01 (n=97). Conclusion: High serum levels of eCIRP are associated with acute respiratory failure in COVID-19. Experimental studies are needed to determine if treatments targeting eCIRP reduces the risk of acute respiratory failure in COVID-19.

Sustained elevation of soluble B- and T- lymphocyte attenuator predicts long-term mortality in patients with bacteremia and sepsis.

Soluble B and T lymphocyte attenuator (sBTLA) has been shown to be associated with severity and outcome, in critically ill septic patients. We aimed to assess the dynamic expression of sBTLA, as a prognostic biomarker of long-term mortality in patients with bloodstream infection (BSI) and sepsis, and to evaluate its association with biomarkers indicative of inflammation and immune dysregulation. Secondarily, sBTLA was evaluated in association with severity and bacterial etiology. Patients with BSI (n = 108) were prospectively included, and serially sampled from admission to day 28. Blood and plasma donors (n = 31), sampled twice 28 days apart, served as controls. sBTLA concentration in plasma was determined with enzyme-linked immunosorbent assay. Associations between sBTLA on day 1-2 and 7, and mortality at 90 days and 1 year, were determined with unadjusted, and adjusted Cox regression. Differences related to severity was assessed with linear regression. Mixed model was used to assess sBTLA dynamics over time, and sBTLA associations with bacterial etiology and other biomarkers. sBTLA on day 1-2 and 7 was associated with mortality, in particular failure to normalize sBTLA by day 7 was associated with an increased risk of death before day 90, adjusted HR 17 (95% CI 1.8-160), and one year, adjusted HR 15 (95% CI 2.8-76). sBTLA was positively associated with CRP, and negatively with lymphocyte count. sBTLA on day 1-2 was not linearly associated with baseline SOFA score increase. High SOFA (≥4) was however associated with higher mean sBTLA than SOFA ≤3. sBTLA was not associated with bacterial etiology. We show that sustained elevation of sBTLA one week after hospital admission is associated with late mortality in patients with BSI and sepsis, and that sBTLA concentration is associated with CRP and decreased lymphocyte count. This suggests that sBTLA might be an indicator of sustained immune-dysregulation, and a prognostic tool in sepsis.

RT-PCR cycle threshold value in combination with visual scoring of chest computed tomography at hospital admission predicts outcome in COVID-19.

BACKGROUND: COVID-19 has a most variable prognosis. Several risk factors for an unfavourable outcome have been identified including extensive lung involvement on chest CT and high viral load estimated by RT-PCR cycle threshold (Ct) values. We investigated Ct value for outcome prediction, relation between Ct value and extent of lung involvement on chest CT and the combination of Ct value and chest CT lung involvement to predict outcome in COVID-19. METHODS: Population-based retrospective study on all patients (n = 286) hospitalised for COVID-19 in Örebro Region, Sweden, between 1 March and 31 August 2020. Nasopharyngeal samples and chest CT at hospital admission were evaluated in relation to outcome of COVID-19. RESULTS: Both Ct value and chest CT lung involvement were independently associated with risk for ICU admission or death. Lung involvement was superior as a single parameter, but addition of Ct value increased the prediction performance. Ct value was especially useful to identify patients with high risk for severe disease despite limited lung involvement. CONCLUSIONS: The addition of RT-PCR Ct value to the assessment of lung involvement on chest CT adds valuable prognostic information in COVID-19. We believe that this information can be used to support clinical decision-making when managing COVID-19 patients.

Clinical measurement of cellular DNA damage hypersensitivity in patients with DNA repair defects.

BACKGROUND: DNA repair deficiency disorders are rare inherited diseases arising from pathogenic (disease-causing) variants in genes involved in DNA repair. There are no standardized diagnostic assays for the investigation of pathological significance of unknown variants in DNA repair genes. We hypothesized that our assays for measuring in vitro patient blood cell hypersensitivity to DNA-damaging agents can be used to establish the pathological significance of unknown variants in DNA repair genes. Six patients with variants in the DNA repair genes PRKDC (two siblings), DCLRE1C (two siblings), NBN, and MSH6 were included. Here, we used the cell division assay (CDA) and the γ-H2AX assay, which were both developed and clinically validated by us, to measure patient cell hypersensitivity in response to ionizing radiation, mitomycin C, cytarabine and doxorubicin. RESULTS: Radiation hypersensitivity was detected in the two patients with variants in the PRKDC gene (p < 0.0001 for both at 3.5 Gy), and the two patients with DCLRE1C variants (p < 0.0001 at 3.5 Gy for sibling 1 and p < 0.0001 at 1 Gy for sibling 2). The cells from the patients with the PRKDC variant were also deficient in removing γ-H2AX (p < 0.001). The cells from the patient with variants in the NBN gene were hypersensitive to mitomycin C (p = 0.0008) and deficient in both induction and removal of γ-H2AX in response to radiation. CONCLUSIONS: The combination of the CDA and the γ-H2AX assay is useful in investigating the significance of unknown variants in some DNA repair genes.

The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity.

The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. We review the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels. Some similarities exist between COVID-19 and respiratory failure of other origins, but evidence for many distinctive mechanistic features indicates that COVID-19 constitutes a new disease entity, with emerging data suggesting involvement of an endotheliopathy-centred pathophysiology. Further research, combining basic and clinical studies, is needed to advance understanding of pathophysiological mechanisms and to characterise immuno-inflammatory derangements across the range of phenotypes to enable optimum care for patients with COVID-19.

Efficacy of the TMPRSS2 inhibitor camostat mesilate in patients hospitalized with Covid-19-a double-blind randomized controlled trial.

BACKGROUND: The trans-membrane protease serine 2 (TMPRSS2) is essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and infection. Efficacy and safety of TMPRSS2 inhibitors in patients with coronavirus disease 2019 (Covid-19) have not been evaluated in randomized trials. METHODS: We conducted an investigator-initiated, double-blind, randomized, placebo-controlled multicenter trial in patients hospitalized with confirmed SARS-CoV-2 infection from April 4, to December 31, 2020. Within 48 h of admission, participants were randomly assigned in a 2:1 ratio to receive the TMPRSS2 inhibitor camostat mesilate 200 mg three times daily for 5 days or placebo. The primary outcome was time to discharge or clinical improvement measured as ≥2 points improvement on a 7-point ordinal scale. Other outcomes included 30-day mortality, safety and change in oropharyngeal viral load. FINDINGS: 137 patients were assigned to receive camostat mesilate and 68 to placebo. Median time to clinical improvement was 5 days (interquartile range [IQR], 3 to 7) in the camostat group and 5 days (IQR, 2 to 10) in the placebo group (P = 0·31). The hazard ratio for 30-day mortality in the camostat compared with the placebo group was 0·82 (95% confidence interval [CI], 0·24 to 2·79; P = 0·75). The frequency of adverse events was similar in the two groups. Median change in viral load from baseline to day 5 in the camostat group was -0·22 log10 copies/mL (p <0·05) and -0·82 log10 in the placebo group (P <0·05). INTERPRETATION: Under this protocol, camostat mesilate treatment was not associated with increased adverse events during hospitalization for Covid-19 and did not affect time to clinical improvement, progression to ICU admission or mortality. ClinicalTrials.gov Identifier: NCT04321096. EudraCT Number: 2020-001200-42.

Visual scoring of chest CT at hospital admission predicts hospitalization time and intensive care admission in Covid-19.

BACKGROUND: Chest CT is prognostic in Covid-19 but there is a lack of consensus on how to report the CT findings. A chest CT scoring system, ÖCoS, was implemented in clinical routine on 1 April 2020, in Örebro Region, Sweden. The ÖCoS-severity score measures the extent of lung involvement. The objective of the study was to evaluate the ÖCoS scores as predictors of the clinical course of Covid-19. METHODS: Population based study including data from all hospitalized patients with Covid-19 in Örebro Region during March to July 2020. We evaluated the correlations between CT scores at the time of admission to hospital and intensive care in relation to hospital and intensive care length of stay (LoS), intensive care admission and death. C-reactive protein and lymphocyte count were included as covariates in multivariate regression analyses. RESULTS: In 381 included patients, the ÖCoS-severity score at admission closely correlated to hospital length of stay, and intensive care admission or death. At admission to intensive care, the ÖCoS-severity score correlated with intensive care length of stay. The ÖCoS-severity score was superior to basic inflammatory biomarkers in predicting clinical outcomes. CONCLUSION: Chest CT visual scoring at admission to hospital predicted the clinical course of Covid-19 pneumonia.

Bridging animal and clinical research during SARS-CoV-2 pandemic: A new-old challenge.

Many milestones in medical history rest on animal modeling of human diseases. The SARS-CoV-2 pandemic has evoked a tremendous investigative effort primarily centered on clinical studies. However, several animal SARS-CoV-2/COVID-19 models have been developed and pre-clinical findings aimed at supporting clinical evidence rapidly emerge. In this review, we characterize the existing animal models exposing their relevance and limitations as well as outline their utility in COVID-19 drug and vaccine development. Concurrently, we summarize the status of clinical trial research and discuss the novel tactics utilized in the largest multi-center trials aiming to accelerate generation of reliable results that may subsequently shape COVID-19 clinical treatment practices. We also highlight areas of improvement for animal studies in order to elevate their translational utility. In pandemics, to optimize the use of strained resources in a short time-frame, optimizing and strengthening the synergy between the preclinical and clinical domains is pivotal.

Early prediction of blood stream infection in a prospectively collected cohort.

BACKGROUND: Blood stream infection (BSI) and sepsis are serious clinical conditions and identification of the disease-causing pathogen is important for patient management. The RISE (Rapid Identification of SEpsis) study was carried out to collect a cohort allowing high-quality studies on different aspects of BSI and sepsis. The aim of this study was to identify patients at high risk for BSI who might benefit most from new, faster, etiological testing using neutrophil to lymphocyte count ratio (NLCR) and Shapiro score. METHODS: Adult patients (≥ 18 years) presenting at the emergency department (ED) with suspected BSI were prospectively included between 2014 and 2016 at Örebro University Hospital. Besides extra blood sampling, all study patients were treated according to ED routines. Electronic patient charts were retrospectively reviewed. A modified Shapiro score (MSS) and NLCR were extracted and compiled. Continuous score variables were analysed with area under receiver operator characteristics curves (AUC) to evaluate the ability of BSI prediction. RESULTS: The final cohort consisted of 484 patients where 84 (17%) had positive blood culture judged clinically significant. At optimal cut-offs, MSS (≥3 points) and NLCR (> 12) showed equal ability to predict BSI in the whole cohort (AUC 0.71/0.74; sensitivity 69%/67%; specificity 64%/68% respectively) and in a subgroup of 155 patients fulfilling Sepsis-3 criteria (AUC 0.71/0.66; sensitivity 81%/65%; specificity 46%/57% respectively). In BSI cases only predicted by NLCR> 12 the abundance of Gram-negative to Gram-positive pathogens (n = 13 to n = 4) differed significantly from those only predicted by MSS ≥3 p (n = 7 to n = 12 respectively) (p < 0.05). CONCLUSIONS: MSS and NLCR predicted BSI in the RISE cohort with similar cut-offs as shown in previous studies. Combining the MSS and NLCR did not increase the predictive performance. Differences in BSI prediction between MSS and NLCR regarding etiology need further evaluation.

Undiagnosed SARS-CoV-2 infection and outcome in patients with acute MI and no COVID-19 symptoms.

OBJECTIVE: We aimed to determine the prevalence and outcome of occult infection with SARS-CoV-2 and influenza in patients presenting with myocardial infarction (MI) without COVID-19 symptoms. METHODS: We conducted an observational study from 28 June to 11 August 2020, enrolling patients admitted to the National Institute of Cardiovascular Disease Hospital, Dhaka, Bangladesh, with ST-segment elevation MI (STEMI) or non-ST-segment elevation MI who did not meet WHO criteria for suspected COVID-19. Samples were collected by nasopharyngeal swab to test for SARS-CoV-2 and influenza virus by real-time reverse transcriptase PCR. We followed up patients at 3 months (13 weeks) postadmission to record adverse cardiovascular outcomes: all-cause death, new MI, heart failure and new percutaneous coronary intervention or stent thrombosis. Survival analysis was performed using the Kaplan-Meier method. RESULTS: We enrolled 280 patients with MI, 79% male, mean age 54.5±11.8 years, 140 of whom were diagnosed with STEMI. We found 36 (13%) to be infected with SARS-CoV-2 and 1 with influenza. There was no significant difference between mortality rate observed among SARS-CoV-2 infected patients compared with non-infected (5 (14%) vs 26 (11%); p=0.564). A numerically shorter median time to a recurrent cardiovascular event was recorded among SARS-CoV-2 infected compared with non-infected patients (21 days, IQR: 8-46 vs 27 days, IQR: 7-44; p=0.378). CONCLUSION: We found a substantial rate of occult SARS-CoV-2 infection in the studied cohort, suggesting SARS-CoV-2 may precipitate MI. Asymptomatic patients with COVID-19 admitted with MI may contribute to disease transmission and warrants widespread testing of hospital admissions.

Presence of hyaluronan in lung alveoli in severe Covid-19: An opening for new treatment options?

Severe coronavirus disease 2019 (Covid-19) is characterized by inflammation of the lungs with increasing respiratory impairment. In fatal Covid-19, lungs at autopsy have been filled with a clear liquid jelly. However, the nature of this finding has not yet been determined. The aim of the study was to demonstrate whether the lungs of fatal Covid-19 contain hyaluronan, as it is associated with inflammation and acute respiratory distress syndrome (ARDS) and may have the appearance of liquid jelly. Lung tissue obtained at autopsy from three deceased Covid-19 patients was processed for hyaluronan histochemistry using a direct staining method and compared with staining in normal lung tissue. Stainings confirmed that hyaluronan is obstructing alveoli with presence in exudate and plugs, as well as in thickened perialveolar interstitium. In contrast, normal lungs only showed hyaluronan in intact alveolar walls and perivascular tissue. This is the first study to confirm prominent hyaluronan exudates in the alveolar spaces of Covid-19 lungs, supporting the notion that the macromolecule is involved in ARDS caused by SARS-CoV-2. The present finding may open up new treatment options in severe Covid-19, aiming at reducing the presence and production of hyaluronan in the lungs.